Genetic and biochemical studies establish a central role of the amyloid precursor protein (APP) in Alzheimer's disease (AD): APP processing generates b-amyloid (Ab) peptides, which are the principal components of the amyloid plaque pathology; mutations in APP are causal for a subset of early onset of familial Alzheimer's disease (FAD). Although b-amyloid plaques are the hallmark of AD, synaptic dysfunction is closely associated with cognitive impairment, and cholinergic neurons undergo profound changes in AD. The mechanisms underlying these pathogenic events are not clearly defined. We reasoned that understanding the physiological function of APP, which thus far remains elusive and controversial, would provide pathogenic insights. To this end, we have created mice deficient in APP and revealed that APP is important in hippocampal synaptic plasticity and cholinergic synapse function. Our recent investigation of the molecular and cellular mechanity and learning and memory. Our current proposal is aimed at deciphering the biochemical and functional mechanisms of these pathways in various neuronal circuitry and investigate the effects of Ab and APP FAD mutations. We are equipped with the novel APP conditional knockout mice and humanized APP/Ab FAD knock-in mice to address these critical questions concerning the pathophysiology of APP in vivo. PUBLIC HEALTH RELEVANCE: APP plays a pivotal role in AD pathogenesis. Deciphering the in vivo function of APP in neurons and synapses and evaluating the effects of b-amyloid peptides and the disease-causing mutations as proposed represents a critical area of AD research. Our studies will provide a comprehensive understanding of the role of APP in various neuronal circuitry and reveal novel pathogenic insights into Alzheimer's disease. 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